AI Article Synopsis
- Cancers with a specific enzyme deletion (ENO1) are sensitive to treatment targeting a related enzyme (ENO2).
- Previous studies showed promise with a specific inhibitor (HEX) that can shrink tumors in certain models of glioblastoma.
- This research aimed to find better prodrug options (forms that release the active drug) for ENO2 inhibition, assessing different types that could be more effective and stable in the bloodstream.
Article Abstract
Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 () are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (), and its bis-pivaloyoxymethyl prodrug, POMHEX (), in an -deleted intracranial orthotopic xenograft model of glioblastoma [ 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in -deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of , exhibited low micromolar IC values in -deleted glioma cells and improved stability in human serum over . The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9620261 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.2c01039 | DOI Listing |
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